In mammal, blood glucose is a synonym of blood sugar. A serious diabetic is required to measure a blood glucose concentration generally 4 to 6 times per day. A general method for measuring the blood glucose concentration is a method of collecting a part of the blood of a patient and analyzing it. However, the analyzing method of frequently collecting the blood greatly burdens the patient and has a possibility that the patient may be infected with an infectious disease through the part where the blood has been collected. Therefore, there is proposed a method of extracting an interstitial fluid present under the skin of a patient through the skin and measuring a glucose concentration in the interstitial fluid collected.
In the present invention, “tissue” means a combination of cells gathered for fulfilling a particular role in vivo and intercellular cements filled therebetween. The tissue of a vertebrate such as human is generally roughly divided into 4 tissues of an epithelial tissue, a supporting tissue (for example, fibrous connective tissue, cartilaginous tissue, bone tissue, blood and lymph), a muscular tissue and a nervous tissue. “Interstitial fluid” generally means a fluid component (also referred to as “intercellular fluid”) present between cells and becoming an environment of the cells in the tissue of a vertebrate such as human.
For example, WO 96/00110 (Patent Literature 1) proposes an ion-introducing device having a collecting reserver having ion conductive hydrogel, first and second ion-introducing electrodes, and a sensor coming into contact with the collecting reserver, and adapted for transferring glucose or a glucose metabolite to the collecting reserver by applying electric energy to percutaneously monitor a target substance. The ion conductive hydrogel of Patent Literature 1 is specifically a crosslinked acrylic acid polymer containing NaCl and NaHCO3 for applying a high ion conductivity.
When a pad composed of the ion conductive hydrogel is struck on the skin of a subject to apply electric energy thereto, an interstitial fluid containing glucose is transferred to the pad through the skin, and the glucose then reacts with a glucose oxidase contained in the ion conductive hydrogel in the pad to generate hydrogen peroxide. A current proportional to the concentration of hydrogen peroxide in the pad is generated in a sensor operating electrode, and this current gives a signal interpreted by a system controller to display the concentration of glucose on a display. Patent Literature 1 describes that when the actual concentration of blood glucose of the subject is measured, that concentration can be correlated with the above-described glucose concentration.
WO 97/02811 (Patent Literature 2) proposes a hydrogel patch comprising a hydrophilic compound forming hydrogel in the presence of water, water in an amount of at most 95% by weight based on the weight of the hydrogel, an enzyme reacting with glucose and an electrolyte. This hydrogel patch is also adopted for measuring a glucose concentration by measuring a current generated by a reaction of the enzyme with glucose like the ion conductive hydrogel described in Patent Literature 1 and is such that transfer of glucose from a subject to the hydrogel patch is also conducted by an electro-osmotic method.
Patent Literature 2 exemplifies polyethylene oxide, polyvinyl alcohol, polyacrylic acid, polyacrylamide methylpropanesulfonate and polyvinyl pyrrolidone as hydrophilic compounds forming hydrogel. The hydrogel of Patent Literature 2 contains a chloride ion-containing salt typified by NaCl as the electrolyte and a glucose oxidase as the enzyme.
When the ion-introducing device or the hydrogel patch disclosed in Patent Literature 1 or Patent Literature 2 is used, an interstitial fluid can be percutaneously extracted by the hydrogel struck on surface of the skin without collecting blood to determine the concentration of glucose contained in the interstitial fluid by analyzing the interstitial fluid collected in the hydrogel after a predetermined period of time has elapsed. When that concentration is correlated with a blood glucose concentration measured by collecting the blood, a value corresponding to the concentration of glucose in the blood can be obtained.
However, the ion-introducing device and the hydrogel patch disclosed in Patent Literatures 1 and 2 both contain a relatively large amount of a sodium ion in the hydrogel for imparting electric conductivity to the hydrogel and an enzyme for metabolizing glucose, such as a glucose oxidase.
When micropores are formed from the surface of the skin to a horny layer by applying electric energy like the technique described in Patent Literatures 1 and 2 for extracting the interstitial fluid using the hydrogel, the amount of glucose in the interstitial fluid collected in the hydrogel varies according to the hole diameter and depth of the micropores, a measured portion on the skin, and the like. Therefore, a value corresponding to the concentration of blood sugar glucose in the blood cannot be exactly obtained by the mere measurement of a glucose concentration in the interstitial fluid, so that in Patent Literature 1, a processing of correlating the measured glucose concentration with a blood glucose concentration measured by actually collecting the blood is conducted.